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Definitions

• Chemokines are a family of low molecular weight proteins (8-13 kDa) that are classified into four distinct groups depending on the positioning of the cysteine motif at the amino terminus.
• the family members comprise CXC, CC, XC, and CX3C chemokines of which CXC and CC are the largest and most characterized.
• the CXC chemokines include interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2), growth-related oncogenes GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , epithelial cell-derived neutrophil activating factor-78 (ENA-78), granulocyte chemoattractant protein-2 (GCP-2), ⁇ -interferon-inducible protein-10 ( ⁇ IP-10), interferon-inducible T cell ⁇ -chemoattractant (I-TAC), monokine induced by ⁇ -interferon (Mig) and platelet factor-4 (PF-4).
• IL-8 interleukin-8
• NAP-2 neutrophil-activating protein-2
• NAP-2 neutrophil-activating protein-2
• GRO- ⁇ epithelial cell-derived neutrophil activating factor-78
• GCP-2 granulocyte chemoattractant protein-2
• ⁇ IP-10 ⁇ -interferon-inducible protein-10
• I-TAC interferon
• CC chemokines include RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory proteins MIP-1 ⁇ , MIP-1 ⁇ , monocyte chemoattractant proteins MCP-1, MCP-2, MCP-3 and eotaxin.
• the XC family comprises two members, lymphotactin- ⁇ and lymphotactin- ⁇ , and the CX3C family consists only of a single chemokine named fractalkine (Murphy et al., Pharmacol. Rev. 52: 145-176, 2000).
• Chemokines mediate their biological effects by binding to cell surface molecules, which belong to the superfamily of seven-transmembrane spanning receptors that signal through coupling to heterotrimeric G proteins. Although most chemokine receptors recognize more than one chemokine, they are almost always restricted to a single subclass. Chemokine receptor binding initiates a cascade of intracellular events of which the first step is the binding of the receptor by its high-affinity ligand. This induces a conformational change leading to a dissociation of the receptor-associated heterotrimeric G proteins into ⁇ and ⁇ subunits.
• G protein subunits are able to activate various effector proteins, including phospholipases leading to generation of inositol trisphosphate, an increase in cytosolic calcium, and activation of protein kinases.
• This cascade of intracellular events mediates a wide range of functions in different leukocytes such as chemotaxis, degranulation, oxidative burst, phagocytosis, and lipid mediator synthesis.
• Interleukin-8 is a key mediator of immunological reactions in inflammatory disorders such as atherosclerosis, ischemia/reperfusion injury, rheumatoid arthritis, chronic obstructive pulmonary disease, respiratory distress syndrome, asthma, cystic fibrosis, and psoriasis (Bizarri et al., Curr. Med. Chem. 2: 67-79, 2003).
• IL-8 is the most characterized member of the CXC subfamily of chemokines. Leukocyte responses to IL-8 are mediated via specific cell surface receptors, CXCR1 and CXCR2.
• CXCR2 responds to several additional chemokines including growth-related oncogenes GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , neutrophil-activating protein-2 (NAP-2), epithelial cell-derived neutrophil activating factor-78 (ENA-78), and granulocyte chemoattractant protein-2 (GCP-2).
• the common denominator shared by all chemokines that activate CXCR2 is a Glu-Leu-Arg (ELR) sequence in the amino terminus, which appears to serve as a recognition sequence for receptor binding and activation (Herbert et al., J. Biol. Chem. 266: 18989-18994, 1991).
• CXCR1 and CXCR2 are thought to be important in several acute neutrophil-mediated diseases such as acute respiratory distress syndrome and ischemia/reperfusion injuries, as well as in chronic diseases such as asthma, psoriasis, dermatitis, and arthritis.
• CXCR2 is also expressed by monocytes. Despite IL-8's inactivity in monocyte chemotaxis assay, this factor induces calcium flux and respiratory burst in monocytes and enhances adhesion of monocytes in static assays. Similarly, GRO- ⁇ enhances adhesion of monocytes to stimulated endothelial cells.
• IL-8 is able to induce firm arrest of monocytes on endothelial cells under conditions of physiological flow (Gerszten et al., Nature 398: 718-723, 1999). Since CXCR2 is strongly expressed on monocytes and macrophages in atherosclerotic lesions where it is suggested to play a key role in chemoattraction, retension, expansion, and activation of monocytes and macrophages, this strongly suggests that CXCR2 and one or more of its ligands (IL-8, GRO- ⁇ ) play a pathophysiological role in atherosclerosis (Huo et al., J. Clin. Invest. 108: 1307-1314, 2001).
• IL-8 receptors Apart from neutrophils and monocytes, numerous cell types have been shown to express IL-8 receptors. These cell types include neurons, various cancer cells, keratinocytes, and endothelial cells. Several lines of evidence indicate that IL-8 plays a direct role in angiogenesis via stimulation of CXCR2 expressed on endothelial cells. IL-8 has been shown to bind specifically to endothelial cells and induce chemotaxis. IL-8 is able to induce neovascularization in the absence of inflammatory responses (Koche et al., Science 258: 1798-1801, 1992).
• IL-8 could play a key role in melanoma progression and metastasis as patients with melanoma metastases have elevated serum levels of IL-8.
• IL-8 is supposed to act as an autocrine growth and metastatic factor for melanoma cells (Schadendorf et al., J. Immunol: 151-157, 1993).
• chemokine receptors CXCR1 and CXCR2 Due to the wide range of actions of IL-8, such as attraction and activation of neutrophils and monocytes/macrophages as well as promotion of endothelial cell proliferation and cancer cell growth, the inhibition of chemokine receptors CXCR1 and CXCR2 is expected to be beneficial in the prevention and treatment of numerous diseases.
• chemokine such as, but not limited to IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2, ENA-78, or GCP-2
• chemokine such as, but not limited to IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2, ENA-78, or GCP-2
• mediated diseases include adult respiratory distress syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, atopic dermatitis, cystic fibrosis, psoriasis, multiple sclerosis, angiogenesis, restenosis, osteoarthritis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, glomerulonephritis, thrombosis, graft vs. host reaction, allograft rejections, alzheimers disease, malaria, viral infections, traumatic brain injury, pulmonary fibrosis, and cancer.
• EP 1 676 834 A1 (Sanofi-Aventis) describes fused bicyclic carboxamide derivatives for use as CXCR2 inhibitors.
• WO 2006/099610 (Wyeth) describes methods for identifying therapeutic targets for the treatment of vulvovaginal atrophy by using heterocyclic compounds including chinolin and isochinolin derivatives.
• WO 2005/070906 (Novartis) describes benzoimidazole derivatives as inhibitors of CXCR2 receptors.
• the invention provides novel compounds represented by the formula I and pharmaceutically acceptable salts, solvates, isomers or prodrugs thereof, which are inhibitors of chemokine receptors, in particular of CXC-chemokine receptors, more particular of CXCR2, and therefore useful for the prevention and treatment of chemokine mediated diseases.
• the invention relates to a compound of formula I
• X in compounds of formula I is described by —CR3 ⁇ CR4-, —CR5 ⁇ N—, —N ⁇ CR6-, —NR7- or —S—, wherein R3, R4, R5 and R6 are independently of one another, hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms, and R7 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, preferably hydrogen; preference is given to compounds, in which X is described by —CR3 ⁇ CR4-, —CR5 ⁇ N—, —N ⁇ CR6-, —NH— or —S—, wherein R3, R4, R5 and R6 are, independently of one another, hydrogen, F, Cl, Br, I or alkyl having 1, 2, 3 or 4 carbon atoms, preferably R3, R4, R5 and R6 are, independently of one another, hydrogen, F, Cl or Br;
• Linker X is attached with its left hand side to the carbon atom in the six-membered ring and with its right hand side to the other carbon atom.
• Y1, Y2, Y3 and Y4 in compounds of formula I are, independently of one another, described by —CR8- or Nitrogen, with the proviso that at least two of Y1, Y2, Y3 and Y4 are defined as —CR8-, wherein R8 is hydrogen, F, Cl, Br, I or alkyl having 1, 2, 3 or 4 carbon atoms; preferably at least three of Y1, Y2, Y3 and Y4 are defined as —CR8, wherein R8 is hydrogen, F, Cl, Br, I or alkyl having 1, 2, 3 or 4 carbon atoms, preferably hydrogen or Cl, for example hydrogen; for example Y1, Y2 and Y3 are CH and Y4 is N or Y1, Y2, Y3 and Y4 are CR8, wherein R8 is hydrogen, F or Cl, in particular hydrogen.
• a in compounds of formula I is described by cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, heterocycle, aryl or heteroaryl, wherein the cycloalkyl or heterocycle radical can be condensed to an aryl radical and wherein the cycloalkyl or heterocycle radical is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, —C(O)-alkyl having 1, 2, 3 or 4 carbon atoms, —C(O)-cycloalkyl having 3, 4, 5 or 6 carbon atoms or —C(O)O-alkyl having 1, 2, 3 or 4 carbon atoms and wherein the aryl or heteroaryl radical can be condensed to an cycloalkyl or heterocycle radical and wherein the aryl or heteroaryl radical is unsubstituted or substituted by 1, 2, 3 or 4 radicals selected from the
• cyclohexyl is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F or alkyl having 1, 2, 3 or 4 carbon atoms, in particular methyl
• the aryl or heteroaryl radical is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, CN, NO 2 , SF 5 , —N(CH 3 ) 2 , methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms, CF 3 , OCF 3 , OCH 2 CF 3 , OCHF 2 , SCH 3 , SOCH 3 , SO 2 CH 3 , SCF 3 , phenyl and benzyl, wherein phenyl can be substituted by Cl.
• the broken line (---) indicates where the substituent A is attached to B.
• A is described as cyclohexyl or an aryl or heteroaryl radical selected from phenyl, naphthyl, indanyl, thienyl, pyridyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiophenyl, benzothiazolyl or quinolyl, wherein cyclohexyl is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F or alkyl having 1, 2, 3 or 4 carbon atoms, in particular methyl, and wherein the aryl or heteroaryl radical is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, SF 5 , methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms, CF 3 , OCF 3 , OCH 2 CF 3 , OC
• A is described by phenyl, pyridyl or benzothiazolyl; which are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, alkyl having 1, 2, 3 or 4 carbon atoms, CF 3 , OCF 3 and SCF 3 ; most particular prefernce is given to compounds, in which A is described by phenyl, pyridyl or benzothiazolyl, which are unsubstituted or substituted by CF 3 , OCF 3 or SCF 3 ; preferably phenyl is stubstituted by CF 3 , OCF 3 or SCF 3 , pyridyl is substituted by CF 3 and benzothiazolyl is unsubstituted.
• a in compounds of formula I is described by unsubstituted cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, heterocycle, aryl or heteroaryl, in which the cycloalkyl or heterocycle radical can be condensed to an aryl radical and in which the aryl or heteroaryl radical can be condensed to an cycloalkyl or heterocycle radical.
• a in compounds of formula I is described by cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, heterocycle, aryl or heteroaryl, wherein the cycloalkyl or heterocycle radical can be condensed to an aryl radical and wherein the cycloalkyl or heterocycle radical is substituted by 1, 2 or 3 radicals and wherein the aryl or heteroaryl radical can be condensed to an cycloalkyl or heterocycle radical and wherein the aryl or heteroaryl radical is unsubstituted or substituted by 1, 2, 3 or 4 radicals; preference is given to compounds of the formula I in which A is described by a monocyclic ring compound, for example a monocyclic cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, heterocycle, aryl or heteroaryl, which is at least substituted once in a position not near to the binding site of the cycloalkyl, heterocycle, aryl or heteroaryl to the linker B, for example
• B in compounds of formula I is described as —O—C(R11R12)-, —C ⁇ C—, —C(R13R14)—C(R15R16)-, —NR17-C(R18R19)- or —NR20-C(O)—, wherein R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are, independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; preference is given to compounds, wherein B is —O—(CR11R12)-, —C ⁇ C— or —CR13R14CR15R16-, wherein R11, R12, R13, R14, R15 and R16 are, independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, preferably when R11, R13, R14, R15 and R16 are hydrogen and R12 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, for
• Linker B is attached with its left hand side to the ring system and with its right hand side to the residue A.
• one or more or all of the groups contained in the compounds of formula I can independently of each other have any of the given, preferred, more preferred or most preferred definitions of the groups specified above or any one or some of the specific denotations which are comprised by the definitions of the groups and specified above, all combinations of given or preferred definitions, more preferred or most preferred and/or specific denotations being a subject of the present invention.
• the compounds of the formula I can be present in the form of their salts.
• An overview of pharmaceutically employed salts can be found in the “Handbook of Pharmaceutical Salts”, edited by P. Heinrich Stahl, Camille G. Wermuth, Verlag Helvetica Chimica Acta, Switzerland, 2002.
• Suitable base addition salts are salts of all pharmacologically acceptable bases, for example alkali metal, earth alkali metal or metal salts, preferably sodium, potassium, magnesium, calcium or zink salts, or as ammonium salts, for example as salts with ammonia or organic amines or amino acids, preferably as salts formed with ammonia, arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylendiamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, lysine, 4-(2-hydroxyethyl)-morpholine, piperazine, 1-(2-hydroxyethyl)-pyrrolidine, triethanolamine or tromethamine; If the compounds contain a basic group, they are capable of forming salts with acid, for example halides, in particular hydrochlorides, hydrobrom
• the compounds of the present invention contain one or more centers of asymmetry, these may independently of one another have the S and the R configuration.
• the compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof in any ratio.
• the compounds of the formula I according to the invention can contain mobile hydrogen atoms, that is be present in various tautomeric forms.
• the present invention relates to all the tautomers of the compounds of the formula I.
• the present invention furthermore encompasses derivatives of compounds of the formula I, for example solvates, such as hydrates and adducts with alcohols, esters, prodrugs and other physiologically tolerated derivatives of compounds of the formula I, and also active metabolites of compounds of the formula I. Further the invention contains all crystal modifications of compounds of formula I.
• the invention relates, in particular, to prodrugs of the compounds of the formula I which are not necessarily pharmacologically active in vitro but which are converted in vivo, under physiological conditions, into active compounds of the formula I, for example by hydrolysis in blood.
• suitable prodrugs for the compounds of the formula I that is chemically modified derivatives of the compounds of the formula I possessing properties which have been improved in a desired manner. Further details with regard to prodrugs can be found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991) 443.
• Prodrugs which are especially suitable for the compounds of the formula I are ester prodrugs of carboxylic acid groups, amide prodrugs of carboxylic acid groups and alcohol prodrugs of carboxylic acid groups as well as acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups, amidino groups and guanidino groups.
• acyl prodrugs or carbamate prodrugs a hydrogen atom which is located on a nitrogen atom is replaced with an acyl group or carbamate group.
• ester prodrugs and amide prodrugs which may be prepared from the carboxylic acid group in a compound of formula I and which may be mentioned are (C 1 -C 4 )-alkyl esters such as methyl esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters and isobutyl esters, substituted alkyl esters such as hydroxyalkyl esters, acyloxyalkyl esters, aminoalkyl esters, acylaminoalkyl esters and dialkylaminoalkyl esters, unsubstituted amides and N—(C 1 -C 4 )-alkylamides, such as methylamides or ethylamides.
• the methyl and ethyl esters of the compounds listed above are included.
• Alkyl radicals may be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkylamino, alkoxy, arylalkyl, heteroarylalkyl, fluoroalkyl or —S-alkyl radicals.
• alkyl radicals are methyl, ethyl, n-propyl, isopropyl ( ⁇ 1-methylethyl), n-butyl, isobutyl ( ⁇ 2-methylpropyl), sec-butyl ( ⁇ 1-methylpropyl), tert-butyl ( ⁇ 1,1-dimethylethyl), pentyl or hexyl.
• Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, tert-butyl and isobutyl. Where indicated, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, hydrogen atoms in alkyl radicals may be replaced by fluorine atoms to form fluoroalkyl radicals. Examples of such radicals are difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl; 3,3,3-trifluoropropyl; 3,3,3-trifluorobutyl, 4,4,4-trifluorbutyl.
• cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, in particular cyclopentyl or cylcohexyl.
• Cycloalkyl radicals can be saturated or partly unsaturated, especially when they are condensed to an aryl or heteroaryl radical.
• a cycloalkyl radical may contain zero, one or two double bonds. This also applies if they carry substituents or occur as substituents of other radicals, for example in the radical cycloalkylalkyl.
• cycloalkyl radicals may be replaced by fluorine atoms to form fluorocycloalkyl radicals.
• Substituted cycloalkyl radicals may be substituted in identical or different positions.
• a cycloalkylalkyl or cycloalkylalkoxy radical the number of carbon atoms has been given, this is the sum of the number of the carbon atoms in the cycloalkyl and in the alkyl or alkoxy radical, respectively.
• Heterocycle radicals are, if not indicated otherwise, monocyclic or bicyclic saturated or partly unsaturated 5, 6, 7, 8, 9 or 10-membered ring compounds in which one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination of various heteroatoms, in particular two oxygen atoms.
• Heterocycle radicals includes heterocycloalkyls and heterocycloalkenyls and, therefore, they can be saturated or partly unsaturated.
• a heterocycle may be condensed to an aryl or heteroaryl radical, for example to form 2,3-Dihydro-benzo[1,4]dioxine.
• a heterocycle radical may contain zero, one or two double bonds.
• the heterocycle radicals may be attached by all positions, for example by the 1 position, 2 position, 3 position, 4 position, 5 position, 6 position, 7 position or 8 position.
• Heterocycle radicals may be unsubstituted or be substituted one or more times, for example once, twice or three times, by identical or different radicals in identical or different positions. This applies likewise to heterocycle radicals such as, for example, in the radical heterocycloalkyl.
• heterocycles are oxirane, aziridine, tetrahydrofurane, tetrahydropyrane, dioxolane, for example 1,3-dioxolane, dioxane, for example 1,4-dioxan, piperidine, pyrrolidin, imidazolidine, triazolidine, hexahydropyrimidine, piperazine, tetrahydropyridazine, triazinane, for example, 1,3,5-triazinane, 1,2,3-triazinane or 1,2,4-triazinane, tetrahydrothiophene, tetrahydrothiopyrane, dithiolane, for example 1,3-dithiolane, dithiane, thiazolidine, oxazolidine, oxathiolane, for example 1,3-oxathiolane, morpholine or thiomorpholine, in particular piperidine, 1,3-
• the aryl radicals are chosen from phenyl, 1-naphthyl, 2-naphthyl and indenyl.
• Aryl radicals may be unsubstituted or be substituted one or more times, for example once, twice or three times, by identical or different radicals. If a aryl radical is substituted, it preferably has one, two or three identical or different substituents. This likewise applies to substituted aryl radicals in groups such as, for example, arylalkyl or aryloxy.
• aryl radicals may be condensed to a cycloalkyl or heterocycle radical, for example to form 2,3-Dihydro-benzo[1,4]dioxine, Benzo[1,3]dioxole or indane.
• Heteroaryl radicals are monocyclic or bicyclic aromatic 5, 6, 7, 8, 9 or 10-membered ring compounds or, where indicated, 5 or 6 membered ring compounds, in which one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination of various heteroatoms.
• the heteroaryl radicals may be attached by all positions, for example by the 1 position, 2 position, 3 position, 4 position, 5 position, 6 position, 7 position or 8 position.
• Heteroaryl radicals may be unsubstituted or substituted one or more times, for example once, twice or three times, by identical or different radicals.
• heteroaryl radicals such as, for example, in the radical heteroarylalkyl.
• heteroaryl radicals may be condensed to a cycloalkyl or heterocycle radical.
• heteroaryl having 5 or 6 atoms are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrazolyl.
• heteroaryls with more atoms examples include benzothiophenyl, benzofuranyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinolizinyl, purinyl, pteridinyl and thienothiazolyl. Also encompassed are the corresponding N-oxides and S-dioxides of these compounds.
• variable e.g. aryl, R1
• its definition on each occurrence is independent of its definition at every other occurrence.
• combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• the invention further relates to the following processes for preparing the compounds of the formula I.
• the procedure for preparing the compounds of the formula I is initially a coupling of an amino compound of formula IV with an acid of formula III for preparing the compound of formula V generally in the presence of an coupling agent, for example EDC, DIC or HATU and optionally an additional base, for example triethylamine or Hünig's base, can be used in an appropriate solvent, in particular in an aprotic polar solvent such as, for example, DMF.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from ⁇ 20° C. to 80°, more preferably from 0° C. to 20° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h depending on the composition of the mixture and the chosen temperature range.
• the transformation of the compound of formula V to the compound of formula VI can be achieved by adding the reagent R-L (Z ⁇ L) in the presence of a suitable base, for example potassium or cesium carbonate.
• L is a leaving group which can undergo nucleophilic substitution, for example Cl, Br, I or OTos.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 20° C. to 150°.
• the reaction time is generally from 2 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• reaction of the compound of formula V with R—OH can be carried out under Mitsunobu conditions, in the presence of, for example, triphenylphosphine and diethylazodicarboxylate (DEAD) or diphenyl-2-pyridylphoshine and diisopropylazodicarboxylate (DIAD).
• DEAD triphenylphosphine and diethylazodicarboxylate
• DIAD diphenyl-2-pyridylphoshine and diisopropylazodicarboxylate
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 80°, more preferably from 0° C. to 25° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the cleavage of the ester of formula VI to the acid of formula Ia in can be achieved in a manner known by the person skilled in the art, for example by the use of a base, like aqueous sodium hydroxide or lithium hydroxide in case of primary or secondary alkyl esters, or for example by the use of an acid, like trifluoroacetic acid in case of tertiary alkyl esters.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 160° C.
• the reaction time is generally from 2 min to 6 days, preferably from 2 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the procedure for preparing the compounds of the formula I is initially a transformation of the compound of formula VII to the compound of formula VIII which can be achieved by adding the reagent R-L (Z ⁇ L) in the presence of a suitable base, for example potassium or cesium carbonate.
• L is a leaving group which can undergo nucleophilic substitution, for example Cl, Br, I or OTos.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 20° C. to 150°.
• the reaction time is generally from 2 min to 6 days, preferably from 15 min to 16 h depending on the composition of the mixture and the chosen temperature range
• the reaction of the compound of formula V with R—OH (Z ⁇ OH) can be carried out under Mitsunobu conditions, in the presence of, for example, triphenylphosphine and diethylazodicarboxylate (DEAD) or diphenyl-2-pyridylphoshine and diisopropylazodicarboxylate (DIAD).
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 80°, more preferably from 0° C. to 25° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the subsequent cleavage of the ester of formula VIII to the acid of formula IX can be achieved in a manner known by the person skilled in the art, for example by the use of a base, like aqueous sodium hydroxide or lithium hydroxide, for example in case of primary or secondary alkyl esters, or by the use of an acid, like trifluoroacetic acid, for example in case of tertiary alkyl esters.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 160° C.
• the reaction time is generally from 2 min to 6 days, preferably from 2 min to 16 h.
• the resulting compound of formula IX can be coupled with the amino compound of formula IV to form the compound of formula VI generally in the presence of an coupling agent, for example EDC, DIC or HATU and optionally an additional base, for example triethylamine or Hünig's base, in an appropriate solvent, in particular in an aprotic polar solvents such as, for example, DMF.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from ⁇ 20° C. to 80°, more preferably from 0° C. to 20° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the optional cleavage of the ester of formula VI to the acid of formula Ia in can be achieved as mentioned above, for example by the use of a base, like aqueous sodium hydroxide or lithium hydroxide, for example in case of primary or secondary alkyl esters, or by the use of an acid, like trifluoroacetic acid, for example in case of tertiary alkyl esters.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 160.
• the reaction time is generally from 2 min to 6 days, preferably from 2 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the procedure for preparing the compounds of the formula I is initially a coupling of an amino compound of formula IV with an acid of formula X for preparing the compound of formula XI generally in the presence of an coupling agent, for example EDC, DIC or HATU and optionally an additional base, for example triethylamine or Hünig's base, can be used in an appropriate solvent, in particular in an aprotic polar solvent such as, for example, DMF.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from ⁇ 20° C. to 80°, more preferably from 0° C. to 20° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h depending on the composition of the mixture and the chosen temperature range.
• a compound of formula V can be converted into a compound of formula XI, in which W is defined as triflate, tosylate or mesylate, by reacting it with an anhydride or chloride of trifluoromethane sulfonic acid para-toluene sulfonic acid or methyl sulfonic acid in the presence of a suitable base, for example triethylamine in an appropriate solvent, for example dichloromethane.
• the reaction temperature in this case is generally from ⁇ 80° C. to 200° C., preferably from ⁇ 20° C. to 80°, more preferably from 0° C. to 20° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h depending on the composition of the mixture and the chosen temperature range.
• the transformation of the compound of formula XI to the compound of formula XII can be achieved by reacting with a reagent V—R, often under inert conditions and in an appropriate solvent, in the presence of a suitable catalytic system, which can contain a palladium and/or copper complex and/or salt, for example Pd 2 dba 3 , Pd(Ph 3 ) 4 , Pd(OAc) 2 or CuI, optionally additional ligands as, for example, phosphine, amine or carbene ligands, and optionally auxiliaries like amines, pyridine, quaternary ammonium salts, CsF, Ag 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOtBu, KOtBu, NaOAc, KOAc, K 3 PO 4 , LiHMDS, NaHMDS or KHMDS.
• a suitable catalytic system which can contain a palladium and/or copper complex and/or
• the reaction temperature in this case is generally from ⁇ 30° C. to 250° C., preferably from 0° C. to 2500, more preferably from 20° C. to 200° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the cleavage of the ester of formula XII to the acid of formula Ib can be achieved in a manner known by the person skilled in the art, for example by the use of a base, like aqueous sodium hydroxide or lithium hydroxide in case of primary or secondary alkyl esters, or for example by the use of an acid, like trifluoroacetic acid in case of tertiary alkyl esters.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 160° C.
• the reaction time is generally from 2 min to 6 days, preferably from 2 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• compounds of formulae Ib and XII in Scheme 3 in which R is defined as —C ⁇ C-A can be (partially) hydrogenated to compounds of formulae Ib and XII, in which R is defined as —CH ⁇ CH-A or —CH 2 CH 2 -A, and compounds of formulae Ib and XII in Scheme 3, in which R is defined as —CR52 ⁇ CR53-A can be hydrogenated to compounds of formulae Ib and XII, in which R is defined as —CHR52 ⁇ CHR53-A.
• transformations can be carried out in analogy to the processes which are described in the literature and are known to those skilled in the art, for example by (partial) hydrogenation of said compounds in the presence of homogenous or heterogenous catalysts.
• the procedure for preparing the compounds of the formula I is initially a transformation of the compound of formula XIII to the compound of formula XIV which can be achieved by reacting with a reagent V—R, often under inert conditions and in an appropriate solvent, in the presence of a suitable catalytic system, which can contain a palladium and/or copper complex and/or salt, for example Pd 2 dba 3 , Pd(Ph 3 ) 4 , Pd(OAc) 2 or CuI, optionally additional ligands as, for example, phosphine, amine or carbene ligands, and optionally auxiliaries like amines, pyridine, quaternary ammonium salts, CsF, Ag 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOtBu, KOtBu, NaOAc, KOAc, K 3 PO 4 , LiHMDS, NaHMDS or KHMDS.
• a suitable catalytic system which can
• the reaction temperature in this case is generally from ⁇ 30° C. to 250° C., preferably from 0° C. to 2500, more preferably from 20° C. to 200° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the subsequent cleavage of the ester of formula XIV to the acid of formula XV can be achieved in a manner known by the person skilled in the art, for example by the use of a base, like aqueous sodium hydroxide or lithium hydroxide, for example in case of primary or secondary alkyl esters, or by the use of an acid, like trifluoroacetic acid, for example in case of tertiary alkyl esters.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 160° C.
• the reaction time is generally from 2 min to 6 days, preferably from 2 min to 16 h.
• a transformation of a compound of formula X to the compound of formula XV can be achieved by reacting with a reagent V—R, often under inert conditions and in an appropriate solvent, in the presence of a suitable catalytic system, which can contain a palladium and/or copper complex and/or salt, for example Pd 2 dba 3 , Pd(Ph 3 ) 4 , Pd(OAc) 2 or CuI, optionally additional ligands as, for example, phosphine, amine or carbene ligands, and optionally auxiliaries like amines, pyridine, quaternary ammonium salts, CsF, Ag2CO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOtBu, KOtBu, NaOAc, KOAc, K 3 PO 4 , LiHMDS, NaHMDS or KHMDS.
• a suitable catalytic system which can contain a palladium and/or copper complex and/or
• the reaction temperature in this case is generally from ⁇ 30° C. to 250° C., preferably from 0° C. to 2500, more preferably from 20° C. to 200° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the resulting compound of formula XV can be coupled with the amino compound of formula IV to form the compound of formula XII generally in the presence of a coupling agent, for example EDC, DIC or HATU and optionally an additional base, for example triethylamine or Hünig's base, in an appropriate solvent, in particular in aprotic polar solvents such as, for example, DMF.
• a coupling agent for example EDC, DIC or HATU and optionally an additional base, for example triethylamine or Hünig's base
• an appropriate solvent in particular in aprotic polar solvents such as, for example, DMF.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from ⁇ 20° C. to 80°, more preferably from 0° C. to 20° C.
• the reaction time is generally from 15 min to 6 days, preferably from 15 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• the cleavage of the ester of formula XII to the acid of formula Ib in can be achieved as mentioned above, for example by the use of a base, like aqueous sodium hydroxide or lithium hydroxide, for example in case of primary or secondary alkyl esters, or by the use of an acid, like trifluoroacetic acid, for example in case of tertiary alkyl esters.
• the reaction temperature in this case is generally from ⁇ 30° C. to 200° C., preferably from 0° C. to 160.
• the reaction time is generally from 2 min to 6 days, preferably from 2 min to 16 h, depending on the composition of the mixture and the chosen temperature range.
• compounds of formulae XIV, XV, XII and Ib in Scheme 4 in which R is defined as —C ⁇ C-A can be (partially) hydrogenated to compounds of formulae XIV, XV, XII and Ib, in which R is defined as —CH ⁇ CH-A or —CH 2 CH 2 -A, and compounds of formulae XIV, XV, XII and Ib in Scheme 4, in which R is defined as —CR52 ⁇ CR53-A can be hydrogenated to compounds of formulae XIV, XV, XII and Ib, in which R is defined as —CHR52 ⁇ CHR53-A.
• These transformations can be carried out in analogy to the processes which are described in the literature and are known to those skilled in the art, for example by (partial) hydrogenation of said compounds in the presence of homogenous or heterogenous catalysts.
• the compounds of formula Ia and Ib are contained in the compound of formula I.
• the workup and optionally the purification of the products and/or intermediates are effected by the customary methods such as extraction, chromatography or crystallization and the customary dryings.
• Functional groups in the starting compounds may be present in protected form or in the form of precursors, and then be converted into the desired groups in the compounds of the formula I prepared by the process described above.
• Corresponding protective group techniques are known to the skilled worker.
• Another aspect of the invention is the use of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients as for producing a medicament for the treatment or prophylaxis of chemokine mediated diseases.
• the invention further relates to the use of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients for producing a medicament for the treatment or prophylaxis of a chemokine mediated disease, wherein the chemokine binds to a CXC receptor.
• Another aspect of the invention is the use of a compound of the formula I and/or the pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients as for producing a medicament for the treatment or prophylaxis of a chemokine mediated disease, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor, in particular to a CXCR2 receptor.
• the invention further relates to the use of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients for producing a medicament for the treatment or prophylaxis of rheumatoid arthritis, chronic obstructive pulmonary disease, adult or acute respiratory distress syndrome, asthma, atherosclerosis, myocardial and renal ischemia/reperfusion injury, peripheral limb ischemia/reperfusion injury, inflammatory bowel disease, ulcerative colitis, Crohn's disease, meconium apriration syndrome, atopic dermatitis, cystic fibrosis, psoriasis, psoriatic arthritis, multiple sclerosis, angiogenesis, restenosis, osteoarthritis, osteoporosis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, glomerulonephritis, thrombosis, graft vs.
• the invention further relates to the use of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients as for producing a medicament for the treatment or prophylaxis of acute and chronic inflammatory diseases such as atherosclerosis, ischemia/reperfusion injuries, chronic obstructive pulmonary disease, asthma, and rheumatoid arthritis, chemokine (such as, but not limited to IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2, ENA-78, or GCP-2) mediated diseases which include adult respiratory distress syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, atopic dermatitis, cystic fibrosis, psoriasis, dermatitis, multiple sclerosis, angiogenesis, restenosis, osteoarthritis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, glomerulone
• certain compounds of formula I may have utility as antagonists of the CX3CR1 receptor.
• Such compounds are expected to be particularly useful in the treatment of disorders within the central and peripheral nervous system and other conditions characterized by an activation of microglia and/or infiltration of leukocytes (e.g. stroke/ischemia and head trauma).
• a medicine or pharmaceutical composition for human or veterinary use comprising an effective amount of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof, together with pharmaceutically acceptable carriers and additives, alone or in combination with other active pharmaceutical ingredients or medicaments.
• Medicaments which comprise a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof can in this connection be administered, for example, orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred administration being dependent on the particular characteristics of the disorder.
• the compounds of the formula I may moreover be used alone or together with pharmaceutical excipients, both in veterinary medicine and in human medicine.
• the medicaments generally comprise active ingredients of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof in an amount of from 0.01 mg to 1 g per dose unit.
• excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge.
• solvents, gel formers, suppository bases, tablet excipients, and other active ingredient carriers it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or colors.
• the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions.
• suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions.
• inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. It is moreover possible for the preparation to take place both as dry granules and as wet granules.
• suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.
• the active compounds used are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion.
• suitable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
• Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents.
• the formulation may, if required, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas.
• Such a preparation normally contains the active ingredient in a concentration of about 0.1 to 10, in particular of about 0.3 to 3% by weight.
• the dosage of the active ingredient of the formula I to be administered, and the frequency of administration, depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the disorder to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
• the daily dose of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 50 mg/kg, preferably 1 mg/kg, of body weight.
• a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to a maximum of 50 mg/kg, preferably 1 mg/kg, of body weight.
• higher and, in particular, more frequent dosages may also be necessary, e.g. up to 4 single doses a day.
• Up to 700 mg a day may be necessary, in particular on i.v. administration, for example for a patient with infarction in the intensive care unit, and the compounds of the invention can be administered by infusion.
• the following example was prepared in analogy to example 2 via a sequence of an alkylation of a suitable (ortho-)hydroxy-arene-carboxylic ester with a corresponding alkylating agent, followed by a basic hydrolysis of this ester, and a coupling of the resulting acid with a corresponding amino acid ester using coupling reagents as for example EDC/HOBT, DIC/HOBT, HATU, TBTU/DMAP, and finally a basic hydrolysis of the amino acid ester to the free amino acid:
• step a) (4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-tetrahydro-thiopyran-4-carboxylic acid methyl ester) from the corresponding (ortho)-hydroxy-arene-carboxylic acids and the corresponding alpha-amino acid methyl, ethyl or tert-butyl esters using coupling reagents as, for example, EDC/HOBT, EDC/HOAT, DIC/HOBT, HATU, TBTU/DMAP, often in the presence of a base like N,N-diisopropylethylamine:
• the assay is based on the detection of intracellular calcium changes detected by the selective, calcium-chelating dye, Fluo-4 (Molecular Probes).
• Fluo-4 Molecular Probes
• a large fluorescence intensity increase is observed upon calcium association with Fluo-4.
• the dye is delivered to the cell interior using an acetoxymethylester form of Fluo-4, where the intracellular esterase activity results in the charged species being released and trapped within the cytoplasm of the cell.
• influx of calcium to this cytoplasmic pocket, via release from intracellular pools and the phospholipase C cascade can be detected.
• activation of this chemokine receptor is directed into this phospholipase C cascade resulting in intracellular calcium mobilization.
• the CHO-K1 cells stably transfected with human CXCR2 and the promiscuous G ⁇ 16 protein were maintained in a log phase of growth at 37° C. and 5% CO 2 in the following media: Iscove's, 10% FBS, 1 ⁇ Penicillin-Streptomycin, 400 ⁇ g/mL G418 and 350 ⁇ g/mL Zeocin.
• 20,000-30,000 cells/well were plated onto a 96-well black/clear bottomed assay plate (Becton Dickinson) with a well volume of 180 ⁇ l.
• the culture medium was carefully removed and replaced by 100 ⁇ l/well dye solution (4 ⁇ M Fluo-4 in 135 mM NaCl, 5 mM KCl, 1 mM magnesium sulphate, 5 mM glucose, 20 mM hepes, 2.5 mM probenecid; pH 7.4).
• Cells were incubated for 1 h at 37° C., and then washed 3 ⁇ with buffer. After washing 90 ⁇ l buffer/well were left.
• Increasing concentrations of compound was added in 45 ⁇ l buffer (4 ⁇ concentrated) followed by 10 min incubation at 37° C.
• the chemokine (10-100 nM) was applied in 45 ⁇ l buffer (4 ⁇ concentrated) and the measurement performed for 2 min.
• the IC50 value of a compound was determined by calculation of % inhibition of total calcium response to the chemokine.
• Compounds of this invention exhibit activity in the CXCR2-calcium fluorescence (FLIPR) assay in a range of about 0.01 nM to 30000 nM. Some compounds of the invention may additionally exhibit activity as modulators of CXCR1 and CX3CR1. CXCR2 inhibition with chemokine IL-8 for selected example compounds:

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• 2007
  • 2007-06-25 WO PCT/EP2007/005574 patent/WO2008000407A1/fr active Application Filing
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